Sulfonated nanohydroxyapatite functionalized with 2-aminoethyl dihydrogen phosphate (HAP@AEPH2-SO3H) as a new recyclable and eco-friendly catalyst for rapid one-pot synthesis of 4,4′-(aryl methylene)bis(3-methyl-1H-pyrazol-5-ol)s

Article abstract of DOI:10.1039/c5ra16236j

Sulfonated nanohydroxyapatite functionalized with 2-aminoethyl dihydrogen phosphate (HAP@AEPH₂-SO₃H), a new green, recyclable solid acid catalyst, was prepared and characterized using FT-IR, XRD, SEM, TEM and TGA/DTA techniques. The

Full text of DOI:10.1039/c5ra16236j

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Graphical Abstract
Sulfonated nanohydroxyapatite functionalized with 2-
aminoethyl dihydrogen phosphate (HAP@AEPH2-SO3H)
as a new recyclable and eco-friendly catalyst for rapid
one-pot synthesis of 4,4'-(aryl methylene)bis(3-methyl-1H-
pyrazol-5-ol)s
Monireh Zarghani, Batool Akhlaghinia
*
HAP@AEPH2-SO3H as a new, green, solid acid catalyst was prepared, characterized and applied for the synthesis of
4,4'-( aryl methylene)bis(3-methyl-1H-pyrazol-5-ol)s.

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Sulfonated nanohydroxyapatite functionalized with 2-aminoethyl
dihydrogen phosphate (HAP@AEPH2-SO3H) as a new recyclable
and eco-friendly catalyst for rapid one-pot synthesis of 4,4'-(aryl
methylene)bis(3-methyl-1H-pyrazol-5-ol)s
Monireh Zarghani, Batool Akhlaghinia*
Abstract: Sulfonated nanohydroxyapatite functionalized with 2ꢀaminoethyl
dihydrogen phosphate (HAP@AEPH2ꢀSO3H) as a new green, recyclable solid acid
catalyst was prepared and characterized by FTꢀIR, XRD, SEM, TEM and TGA/DTA
techniques. Composition of HAP@AEPH2ꢀSO3H was determined as
nonohydroxyapatite, while particles were observed to have nanorods morphology.
Size estimations using TEM (10ꢀ100 nm) and the crystallinity using XRD (hexagonal
phase) are wellꢀmatched to character of nanohydroxyapatite. The catalytic activity of
HAP@AEPH2ꢀSO3H was evaluated for synthesis of 4,4'ꢀ(aryl methylene)bis(3ꢀ
methylꢀ1Hꢀpyrazolꢀ5ꢀol)s via oneꢀpot reactions of phenylhydrazine/or hydrazine
hydrate, ethylacetoacetate and aldehydes under solventꢀfree condition. This catalyst
showed notable advantages such as environmental friendliness, excellent yields,
shorter reaction time, reusability of inexpensive catalyst and easy workup procedure.
Keywords: HAP@AEPH2ꢀSO3H, 4,4'ꢀ(aryl methylene)bis(3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀ
ol)s, oneꢀpot reaction, green chemistry
1

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Introduction
4,4′ꢀ(Aryl methylene)bis(1Hꢀpyrazolꢀ5ꢀol)s as an important class of heterocyclic
compounds have been exhibited a wide range of biological activities such as
antimalarial,1 antifungal,2 antiꢀinflammatory,3 antimicrobial,4 antinociceptive,5
antivirals,6 and antitumor7 activities. Also, they are used as pesticides,8 fungicide,9
analgesic,10 important intermediates in organic synthesis11 bisꢀSchiff bases12 and
ligands.13 The conventional chemical approach to 4,4′ꢀ(aryl methylene)bis(1Hꢀ
pyrazolꢀ5ꢀol)s derivatives is the reaction of initially formed 3ꢀmethylꢀ5ꢀpyrazolone
(from the condensation of hydrazine /aryl hydrazine and ethyl acetoacetate) with
aldehydes under a variety of reaction conditions. Xanthan sulfuric acid,14
phosphomolybdic acid,15 silica sulfuric acid,16 3ꢀaminopropylated silica gel,17 sodium
dodecyl sulfate,18 tetramethylꢀtetraꢀ3,4ꢀpyridinoporphyrazinato copper(II) methyl
sulfate,19 poly(ethylene glycol)ꢀbound sulfonic acid,20 and others21ꢀ32 can be used as
catalysts for this transformation. Catalyst free33 and electrocatalytic procedure34 were
also used for this preparation. Other methods of preparation include oneꢀpot reactions
in which three or more starting materials react together to form a product where all or
most of the starting material atoms exist in the final product.35 In comparison, the oneꢀ
pot character also, provides some advantages over the classical stepwise synthetic
routes such as fewer byꢀproducts, lower costs, time, and energy. Recently because of
simple purification, excellent synthetic efficiency, atom economy, operational
simplicity, elimination of overflow steps and environmental friendliness, oneꢀpot
reactions have been paid much attention.36 Also, oneꢀpot reactions offer formation of
complex molecular architectures from simple precursors via formation of several
bonds in a simple synthetic operation, without the need for isolation of
intermediates.37 However, a few methods have been reported for the synthesis of these
2

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compounds by oneꢀpot reactions in the presence of silicaꢀbonded Nꢀpropylpiperazine
sulfamic acid (SBPPSA),38 pyridine trifluoroacetate,39 N,2ꢀdibromoꢀ6ꢀchloroꢀ3,4ꢀ
dihydroꢀ2H benzo[e][1,2,4]thiadiazineꢀ7ꢀsulfonamide 1,1ꢀdioxide (DCDBTSD),40
ultrasonic irradiation,41 sulfonated rice husk ash (RHAꢀSO3H),42 2ꢀhydroxy
ethylammonium propionate (2ꢀHEAP).43
In recent years, to minimize the use and production of hazardous materials, green
chemistry encourages chemists to design chemical procedures by using
environmentally benign reagents that reduce and prohibit the pollution of nature and
ensure perpetual life on the earth.44 Because of usefulness of oneꢀpot reactions for the
synthesis of complex molecules such as drugꢀlike molecules, these kind of reactions
play an important role in combinatorial chemistry and industrial chemistry.45, 46
Over the past decades, to overcome some problems of homogeneous catalytic
processes, heterogeneous catalysts such as mixed metal oxides, zeolites, hydrotalcites,
solidꢀsupported catalysts, resins, etc are particularly attractive, because of possessing
advantages such as ease of separation of product, reusability of the catalyst and
improved efficiency. On the other hand, heterogeneous catalysts which has been
known for many years has become strategically vital for efficient and ecofriendly
organic transformations. Among various heterogeneous catalysts, nanohydroxyapatite
(nanoHAP [Ca10(PO4)6(OH)2]) as an important inorganic nanomaterial with high
surface area and low particle size, provide high biocompatibility, great catalytic
activity and good adsorption capability. It has been reported that the functional
groups, pH, and charge on the surface of nanoHAP have great effects on its surface
properties.47 Therefore, to improve the practical applications of nanoHAP as catalyst
in organic synthesis, the modification surface of nanoHAP with functional groups is
an effective method to obtain the unique nanoHAP properties. The use of
3

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organophosphates, mostly alkylphosphates for surface modification of nanoHAP have
been described previously.48 It has been found that, there are strong interactions
between the phosphonic groups of organophosphates with PꢀOH and perhaps CaꢀOH
groups on the surface of nanoHAP which leads to formation of PSꢀOꢀP and PꢀOꢀ Ca2+
bonds.48c 2ꢀAminoethyl dihydrogen phosphate (AEPH2) as a fairly unknown
phospholipid and biodegradable compound can be used as a surface modification
agent. AEPH2 is a bifunctional organic molecule that has both a phosphate group and
an amino group.49 Therefore, the phosphate group can be used for binding to
nanoHAP surface and the amino group can also work as an anchoring point for
bonding of several metal ions, and other functional groups. In continuing our efforts
toward the development of efficient and environmentally benign heterogeneous
catalysts,50 herein, we designed nanoHAP that is modified with AEPH2 as ligand and
then sulfonated with chlorosulfonic acid (HAP@AEPH2ꢀSO3H) (Scheme 1). The
catalytic activity of HAP@AEPH2ꢀSO3H as an ecoꢀfriendly, reusable heterogeneous
catalyst was proved for the synthesis of 4,4'ꢀ( aryl methylene)bis(3ꢀmethylꢀ1Hꢀ
pyrazolꢀ5ꢀol)s via oneꢀpot reaction (see Scheme 2).
4

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Scheme 1 Preparation steps of HAP@AEPH2ꢀSO3H.
Results and Discussion
Characterization of catalyst
According to the pathway shown in Scheme 1, HAP@AEPH2ꢀSO3H as a novel strong
and stable solid acid catalyst was synthesized. The structure and morphology of the
prepared catalyst was characterized by Fourier transform infrared spectroscopy (FTꢀ
IR), thermogravimetric analysis (TGA), differential thermal analysis (DTA), scanning
5

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electron microscopy (SEM), elemental analysis (CHN), transmission electron
microscopy (TEM) and Xꢀray powder diffraction (XRD) which confirmed the
successful preparation of the new catalyst.
In order to confirm the successful functionalization of nanoHAP with AEPH2 and
then with chlorosulfuric acid, FTꢀIR spectra of HAP@AEPH2 and HAP@AEPH2ꢀ
SO3H were recorded (Figure 1). Figure 1a depicts the FTꢀIR spectrum of the
nanoHAP functionalized with AEPH2. As can be seen, the stretching and bending
vibration of OH− ion in hydroxyapatite were detected around 3572 and 630 cm−1
respectively. Also, the broad band at 3450ꢀ3050 cm−1 (due to stretching vibration) and
the weak band at 1637–1630 cm−1 (due to bending vibration) were attributed to the
crystal water and surface adsorbed water. Additional vibrational modes at 1098, 1031,
962, 601, 571, and 471 cm−1 could be ascribed to the asymmetric, symmetric
3−
stretching and bending vibrations of the PO4 ions respectively.51 In addition to the
principal absorption bands of nanoHAP, appearance of two absorption bands at 2917
and 2851 cmꢀ1 due to asymmetric and symmetric vibrational frequencies of ꢀCH2,
confirmed the successful attachment of AEPH2 on the surface of the nanoHAP
(Figure 1 a).52 In FTꢀIR spectrum of HAP@AEPH2ꢀSO3H (Figure 1 b), the intensity
of absorption band at 3450ꢀ3050 cm−1 was increased because of the presence of more
OH groups which appeared after sulfonation. Furthermore, as compared with Figure
1a, we can see some new absorption bands at 1325 and 1155 cmꢀ1 which are attributed
to the asymmetric and symmetric stretching frequencies of S=O.53 These absorption
bands reveal that ꢀSO3H group has been successfully grafted onto the surface of
HAP@AEPH2.
6

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Figure 1. FTꢀIR spectrum of (a) HAP@AEPH2 and (b) HAP@AEPH2ꢀSO3H.
The crystallinity and phase identification of the HAP@AEPH2 and HAP@AEPH2ꢀ
SO3H were determined by using Xꢀray diffraction (XRD). As presented in Figure 2,
the characteristic peaks with strong intensities appeared at angles corresponding to
(002), (211), (300), (202), (310), (222), (213) and (004) crystallographic faces which
are in agreement with the standard data of nanoHAP (JCPDS: 74ꢀ0565).54 The XRD
results also demonstrate the presence of hexagonal phase nanoHAP with high
crystallinity.
Although XRD analysis of the HAP@AEPH2ꢀSO3H showed no considerable
broadening or shifting of peaks when compared with the XRD of HAP@AEPH2
(Figure 2) but an additional peak observed in the HAP@AEPH2ꢀSO3H pattern at 2θ =
25.4° could be be attributed to a little impurity CaSO4 due to sulfonation (JCPDS: 37ꢀ
1496) (Figure 2b). 55
7

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In spite of this, it could be seen that the modification of the nanoHAP with AEPH2
and chlorosulfuric acid did not change the crystal structure of the nanoHAP.
(211)
(201)
(002)
(300)
(202)
(213)
(310) (222)
(004)
(b)
(a)
10
20
30
40
50
60
70
80
2-Theta-Scale
Figure 2. The XRD patterns of (a) HAP@AEPH2 and (b) HAP@AEPH2ꢀSO3H.
In addition, scanning electron microscopic and transmission electron microscopic
(SEM and TEM) images were used to investigate the morphology and size of
HAP@AEPH2ꢀSO3H nanoparticles. Figures 3a and 3b represent the SEM
micrographs of HAP@AEPH2ꢀSO3H nanoparticles. These images demonstrate that
HAP@AEPH2ꢀSO3H nanoparticles have uniform nanorods morphology which are
similar to the particle morphologies reported elsewhere.56 The TEM images of the
HAP@AEPH2ꢀSO3H nanoparticles shown in Figures 3c and 3d revealed that
synthesized nanoparticles are rod in shape with a mean size range of 10ꢀ100 nm. They
also indicate that in comparison with literature57 there is no change in the shape of
nanoHAP after being functionalized with AEPH2 and sulfonic acid and the surface
morphology is also retained.
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Figure 3. (a, b) SEM images of HAP@AEPH2ꢀSO3H, (c, d) TEM images of
HAP@AEPH2ꢀSO3H.
Quantitative determination of the organic functional groups loaded on the surface of
nanoHAP was studied by TGA and DTA (Figure 4). For HAP@AEPH2, weight loss
º
at temperatures below 200 C (4.00 %) is probably related to the physically adsorbed
water on the catalyst surface. Also, the weight loss from 200 to 500ºC is associated
with the decomposition of AEPH2 groups grafted to the nanoHAP surface (Figure 4
a).58 The TGA curve of HAP@AEPH2ꢀSO3H (Figure 4 b) shows a three weight loss
º
steps. The initial weight loss up to 200 C is due to absorbed water, second step
º
involves the decomposition of AEPH2 which started after 200 C and continued up to
9

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º
º
º
500 C. The last step can be observed between 500 C and 850 C, corresponding to
the thermal decomposition of SO3H groups embedded via AEPH2 on the surface of
nanoHAP.59
According to the TGA curves, it can be estimated that the amount of AEPH2 and
sulfonic acid functionalized into the surface of catalyst are about 5.60 and 8.00 %
respectively.
Figure 4. The TGA/DTA Thermograms of (a) HAP@AEPH2 (b) HAP@AEPH2ꢀ
SO3H.
In addition to the TGA/DTA analysis, the contents of AEPH2 and sulfonic acid were
also determined by elemental analysis (Table 1). As can be seen in Table 1, the
elemental analysis of the catalyst indicated that 1.008 mmol of AEPH2 and 1.040
mmol of sulfonic acid are incorporated into 1.000 g of HAP@AEPH2ꢀSO3H which is
in good agreement with the data obtained from TGA.
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Table1 TGA and elemental analysis data of HAP@AEPH2 and HAP@AEPH2ꢀSO3H.
TGA (%)
AEPH2
Elemental analysis (w/w %)
Samples
H2O
SO3H
ꢀ
C
N
S
ꢀ
HAP@AEPH2
4.000
(2.200
5.600
(1.010
2.409
(1.004
1.397
(1.000
mmol/g)
mmol/g)
mmol/g)
mmol/g)
HAP@AEPH2
ꢀSO3H
4.000
(2.200
5.600
(1.010
8.000
(1.065
2.419
(1.008
1.409
(1.007
3.32
(1.040
mmol/g)
mmol/g)
mmol/g)
mmol/g)
mmol/g)
mmol/g)
Moreover, the amount of acidic sites in HAP@AEPH2ꢀSO3H was determined by
backꢀtitration analysis of the catalyst: 100 mg of catalyst was added to a solution of
NaOH (15 mL, 0.1 N).The resulting suspension was maintained at room temperature
overnight under stirring. After that the suspension was filtered. The filtrate was
neutralized by a standard solution of HCl (0.1 M). The consumed volume of HCl
(14.1 mL) determined the amount of loaded NHSO3H per 1.000 g of HAP@AEPH2ꢀ
SO3H (0.900 mmol of NHSO3H per 1.000 g of catalyst). This result is in good
agreement with those of the results obtained from TGA and elemental analysis.
Catalytic synthesis of 4,4'-(aryl methylene)bis(3-methyl-1H-pyrazol-5-ol)
In continuation of our studies to develop the new catalysts for organic
transformations50 and to replace the conventional, toxic and polluting BrÖnsted acid
catalysts with ecoꢀfriendly, reusable, heterogeneous catalysts, HAP@AEPH2ꢀSO3H
was used as solid acid catalyst in oneꢀpot preparation of 4,4'ꢀ(aryl methylene)bis(3ꢀ
methylꢀ1
H
ꢀpyrazolꢀ5ꢀol)s
from
phenylhydrazine/or
hydrazine
hydrate,
ethylacetoacetate and aldehydes (Scheme 2).
11

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Scheme 2 Oneꢀpot synthesis of 4,4'ꢀ(aryl methylene)bis(3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀol)s
catalyzed by HAP@AEPH2ꢀSO3H.
To find an appropriate reaction medium for the synthesis of 4,4'ꢀ(aryl
methylene)bis(3ꢀmethylꢀ1 ꢀpyrazolꢀ5ꢀol)s in the presence of a catalytic amount of
H
HAP@AEPH2ꢀSO3H, one pot reaction between phenylhydrazine (2 mmol), ethyl
acetoacetate (2 mmol) and benzaldehyde (1 mmol) was selected as a model reaction.
The model reaction was examined under different reaction conditions such as:
different solvents, different temperatures and various amounts of catalyst (Table 2). A
blank experiment without catalyst under solventꢀfree conditions at 80 ºC gave very
low yield (10 %) after 24 h (Table 2, entry 1). The efficient catalytic activity of
HAP@AEPH2ꢀSO3H was confirmed by performing the model reaction in the
presence of nanoHAP and nanoHAPꢀNH2. The desired product was scarcely obtained
(20 %) in the presence of nanoHAP and nano HAPꢀNH2 under solventꢀfree conditions
at 80 ºC (Table 2, entries 2ꢀ3). Applying 2 mol % of HAP@AEPH2ꢀSO3H (contains
0.02 mmol of acid) under solventꢀfree conditions at 80 ºC produced 4,4'ꢀ
(phenylmethylene)bis(3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀol) in high yield after 2 (min) (Table 2,
entry 4). We examined the effect of different temperatures on the model reaction
under solvent free condition. The reactions took a long time to achieve high yield of
the desired product (Table 2, entries 5ꢀ8). To evaluate the effect of different amounts
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of HAP@AEPH2ꢀSO3H, the model reaction was performed in the presence of 1 mol
% (contains 0.01 mmol of acid) and 1.5 mol % (contains 0.015 mmol of acid) of
catalyst (Table 2, entries 9ꢀ10). Best result was obtained by applying 1.5 mol % of
catalyst under solvent free conditions at 80 ºC. To examine the effect of solvent,
various solvents were screened (H2O, EtOH, H2O/EtOH (1/1) and CH3CN) in the
preparation of 4,4'ꢀ(phenylmethylene)bis(3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀol) in the presence
of 1.5 mol % of HAP@AEPH2ꢀSO3H (Table 2, entries 11–14). It is observed that
solventꢀfree conditions gave the best result for this transformation.
Table 2 Synthesis of 4,4'ꢀ(phenylmethylene)bis(3ꢀmethylꢀ1
Hꢀpyrazolꢀ5ꢀol) in the
presence of HAP@AEPH2ꢀSO3H under different reaction conditions.
Entry
1
Catalyst
(mol %)
Solvent
Temperature
(˚C)
Time
(min)
Isolated Yield (%)
10
ꢀ
Solventꢀfree
80
24(h)
2*
2
2
Solventꢀfree
Solventꢀfree
80
80
3(h)
3(h)
20
20
3**
4
5
6
7
2
2
2
2
Solventꢀfree
Solventꢀfree
Solvent free
Solventꢀfree
80
70
60
40
2
98
92
94
95
6
10
45
8
2
Solventꢀfree
Solventꢀfree
Solventꢀfree
H2O
r.t
80
80
80
80
80
2(h)
10
3
45
95
98
75
70
65
9
1
10
11
12
13
1.5
1.5
1.5
1.5
10
15
15
EtOH
H2O/ EtOH
(1:1)
14
1.5
CH3CN
80
10
75
13

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*
The reaction was performed in the presence of nanoHAP.
** The reaction was performed in the presence of nanoHAPꢀNH2.
In the next step, to explore the scope and efficiency of this oneꢀpot reaction, with this
result in hand, we examined a range of various aromatic aldehydes under the
optimized reaction conditions. For this purpose, phenyl hydrazine/ or hydrazine (2
mmol), ethylacetoacetate (2 mmol) and a broad range of structurally diverse aromatic
aldehydes (1 mmol) were condensed in the presence of 1.5 mol % of HAP@AEPH2ꢀ
SO3H to achieve the desired product. The results are summarized in Table 3.
Aromatic aldehydes (bearing electron withdrawing and electronꢀdonating groups) led
to rapid formation of products 3aꢀ3q (Table 3, entries 2ꢀ17) in high yields. Also
heteroaromatic aldehydes such as pyridine carboxaldehydes, and allylic aldehydes
such as cinnamaldehyde led to products 3r (94 %), 3s (93 %), and 3t (90 %)
respectively (Table 3, entries 18ꢀ20).
We also used hydrazine instead of phenylhyrazine in this reaction (Table 3, entries
21ꢀ23). The desired products were also obtained rapidly in excellent yields.
Table 3 Preparation of 4, 4′ꢀ(aryl methylene)bis(1
Hꢀpyrazolꢀ5ꢀol)s derivatives
catalyzed by HAP@AEPH2ꢀSO3H under solventꢀfree conditions at 80 ºC.
Entry
R1
R2
Product Time
(min)
Isolated
Yield (%)
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1
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3a
3b
3c
3d
3e
3f
3
2
3
4
3
7
5
7
7
5
7
3
7
2
3
5
5
2
3
98
95
93
90
98
93
93
85
92
80
80
98
85
97
80
80
95
94
93
4ꢀOHC6H4
3ꢀOHC6H4
2ꢀOHC6H4
4ꢀOMeC6H4
3ꢀOMeC6H4
4ꢀMeC6H4
3ꢀMeC6H4
3
4
5
6
7
3g
3h
3i
8
9
C6H5 5ꢀBrꢀ2ꢀOHC6H3
10
11
12
13
14
15
16
17
18
19
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4ꢀiPrC6H4
2ꢀClC6H4
3j
3k
3l
4ꢀClC6H4
2,4ꢀ(Cl)2C6H3
4ꢀBrC6H4
3m
3n
3o
3p
3q
3r
3ꢀNO2C6H4
2ꢀNO2C6H4
1ꢀNaphthyl
2ꢀPyridyl
3ꢀPyridyl
3s
20
21
22
23
C6H5
H
C6H5CH=CH2
C6H5
3t
3u
3v
3w
5
10
8
90
98
98
95
H
4ꢀClC6H4
4ꢀMeC6H4
H
10
15

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The structures of all synthesized compounds 3a–w have been established by their
1
melting points, FTꢀIR spectroscopy and H NMR spectroscopy. Moreover, the
selected compounds were further identified by 13C NMR spectroscopy, mass
spectrometry and elemental analysis.
The FTꢀIR spectrum of purified products displayed characteristic signals for OH,
C=N and C=C bonds around 3450ꢀ2500, 1600 and 1499 cmꢀ1 respectively. Also, the
1H NMR spectra exhibited a sharp singlet resonating at around 5.50ꢀ4.89 ppm due to
aryl methylene proton and two broad peaks around 13.91 and 12.40 ppm revealed two
13
–OH groups. In C NMR spectra, a signal at 32 ppm is assigned to aryl methylene
carbon. The elemental analysis of the synthesized compounds was also in good
conformity with the proposed structures.
To further elucidate the structure of products, mass spectrometry was provided. As
can be seen, molecular ion was not evident in some of mass spectra because of the
very facile cleavage of CꢀC bond between aryl methylene carbon and pyrazole ring.
However, some useful fragmentation information for each compound has been
described, which can be beneficial for depicted desired products.
A reasonable mechanism for the formation of 4,4′ꢀ(aryl methylene)bis(1Hꢀpyrazolꢀ5ꢀ
ol)s derivatives is proposed in Scheme 3. The reaction involves the initial formation
of pyrazolone (VI) (which is in equiblirium with its other tautomeric form (VII)) by
the reaction between the protonated form of ethylacetoacetate (I) and phenyhydrazine/
or hydrazine. Afterwards in acidic media, condensation of the intermediate (VII) with
aldehyde and subsequent dehydration, lead to formation of IX. A Michael addition
reaction between IX and VII, produced two tautomeric forms XI and XII followed by
releasing of the acidic catalyst. Then the solid acid catalyst reꢀenters to the catalytic
cycle.
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Among various reactions, we found that in the reaction between 4ꢀMe2NꢀC6H4ꢀCHO
and 3ꢀmethylꢀ1ꢀphenylꢀ1 ꢀpyrazolꢀ5ꢀol (VII), no desired product was obtained.
Instead, )ꢀ4ꢀ(4ꢀ(dimethylamino)benzylidene)ꢀ3ꢀmethylꢀ1ꢀphenylꢀ1 ꢀpyrazolꢀ
5(4 )ꢀone as product was formed, which was established by FTꢀIR, mass spectrum
H
(E
H
H
1
and H NMR spectrum (see supporting information ) (Scheme 3). This effect can be
explained by conjugative effect that is responsible for greater stability as compared to
its analogues (formed by use of other aldehydes).60
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Scheme 3 Proposed mechanism for the synthesis of 4,4'ꢀ(aryl methylene)bis(3ꢀ
methylꢀ1Hꢀpyrazolꢀ5ꢀol)s using solid acid catalyst (HAP@AEPH2ꢀSO3H).
In another study, the reusability of the catalyst that is one of the most important
benefits and makes it useful for commercial applications was examined upon model
reaction. In this experiment, after completion the reaction, the reaction mixture was
boiled in EtOAc and then centrifuged to separate the catalyst. To remove all organic
compounds, the catalyst was refluxed in EtOAc (3×10) and centrifuged consecutively.
The recycled catalyst was dried at 50 ºC under vacuum for 3 h and used in the next
run of the model reaction. The results of this experiment and five subsequent
experiments were almost consistent in yields (97, 97, 94, 92, 85 %). Although slightly
more time was required to complete the reaction in the fifth run, the yields are
comparable to those seen earlier (Figure 5). Elemental analysis of reused catalyst (C
2.398 %, N 1.368 %, S 3.101 %) showed that there was no significant leaching of
ligand AEPH2 from catalyst to the reaction mixture but a little leaching SO3H can be
observed away from the surface of catalyst after five runs of reaction.
100
100
98
97
97
100
95
90
85
80
75
70
65
60
94
95
92
90
85
First
Second
Third
Fourth
Fifth
Conversion*
Isolated Yield
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Figure 5. Synthesis of 4,4'ꢀ(phenylmethylene)bis(3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀol) in the
presence of reused HAP@AEPH2ꢀSO3H.
*The data referred to conversion of benzaldehyde.
We compared the efficiency of HAP@AEPH2ꢀSO3H with the previously reported
catalysts in literature which applied in oneꢀpot preparation of 4,4′ꢀ(aryl
methylene)bis(1Hꢀpyrazolꢀ5ꢀol)s derivatives. The results are shown in Table 4. It is
clear from Table 4 that HAP@AEPH2ꢀSO3H promoted the reaction more effectively
than a number of other catalysts, particularly in terms of the reaction yield and also
the time required to complete the reaction.
Table 4 Comparison efficiency of various catalysts in the synthesis of 4,4'ꢀ( aryl
methylene)bis(3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀol)s via oneꢀpot reaction.
Entry
1
Catalyst
Solvent
Temperature
(°C)
Time
(min)
Yield
(%)
Reference
45
Ultrasonic
irradiation
H2O/EtOH(1:1)
R.T
15
98
2
3
2ꢀHEAP*
Solventꢀfree
Solventꢀfree
90
80
30
45
91
93
47
42
SBPPSA**
4
5
6
RHAꢀSO3H
Solventꢀfree
Solventꢀfree
Solventꢀfree
80
80
80
3
100
3
91
74
98
46
44
DCDBTSD***
HAP@AEPH2ꢀ
SO3H
Present
study
* 2ꢀHydroxy ethylammonium propionate (2ꢀHEAP)
** Silicaꢀbonded Nꢀpropylpiperazine sulfamic acid (SBPPSA)
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***N, 2ꢀDibromoꢀ6ꢀchloroꢀ3,4ꢀdihydroꢀ2H benzo[e][1,2,4]thiadiazineꢀ7ꢀsulfonamide 1,1ꢀdioxide
(DCDBTSD)
Experimental
General
The purity determinations of the products were accomplished by TLC on silica gel
polygram STL G/UV 254 plates. The melting points of products were determined
with an Electrothermal Type 9100 melting point apparatus. The FTIR spectra were
recorded on pressed KBr pellets using a AVATAR 370 FTꢀIR spectrometer (Therma
Nicolet spectrometer, USA) at room temperature in the range between 4000 and 400
cm−1 with a resolution of 4 cm−1, and each spectrum was the average of 32 scans.
NMR spectra were recorded on a NMR Bruker Avance spectrometer at 400 and 300
MHz in DMSOꢀd6 as solvent in the presence of tetramethylsilane as internal standard.
Elemental analysis was performed using a Thermo Finnigan Flash EA 1112 Series
instrument (Furnace: 900 oC, Oven: 65 oC, Flow Carrier: 140 mL/min, Flow Referece:
100 mL/min). Mass spectra were recorded with a CH7A Varianmat Bremem
instrument at 70 eV electron impact ionization, in m/z (rel %). TGA and DTA analysis
were performed using a Shimadzu Thermogavimetric Analyzer (TGꢀ50) in the
temperature range of 25ꢀ900 ºC at a heating rate of 10 ºC /min under air atmosphere.
SEM images were recorded using Leo 1450 VP scanning electron microscope
operating at an acceleration voltage 20 kV, resolution of about 2 nm, image with a
magnification of 20 to 300,000 times (LEO, Germany). Transmission electron
microscopy (TEM) was performed with a Leo 912 AB microscope (Zeiss, Germany)
with an accelerating voltage of 120 kV, image with a magnification of 80 to 500,000
times, equipped with a high resolution CCD Camera. The crystal structure of catalyst
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was analyzed by XRD using a D8 ADVANCE –Bruker diffractometer operated at 40
kV and 30 mA utilizing CuKɑ radiation (λ= 0.154 Aº), at a step size of 0.040 º and
step time of 1.5 s. The diffraction angles (2θ) were scanned from 10 º to 80 º. All
yields refer to isolated products after purification by recrystallization.
Preparation of nanoHAP functionalized with AEPH2 (HAP@AEPH2)
To a solution of Ca(NO3)2.4 H2O (50 mL, 1.08 M, at pH adjusted to 10 with NH4OH )
in a threeꢀnecked 500 mL roundꢀbottomed flask equipped with condenser, argon gas
inlet tube and dropping funnel, solution of (NH4)2HPO4 (50 mL, 0.65 M at pH
adjusted to 10 with NH4OH) was added at 90 °C with stirring. AEPH2 (0.8 g, 5 mmol)
was added to the resulting suspension. The precipitate was maintained in contact with
the reaction solution for 5 h at 90 °C under stirring. Then suspension was centrifuged
at 10,000 rpm for 10 min and repeatedly washed with CO2ꢀfree distilled water (3 × 20
mL). The product (nanoHAP functionalized with AEPH2) was dried at 50 °C
overnight. 48d
Preparation of HAP@AEPH2-SO3H
To a magnetically stirred mixture of HAP@AEPH2 (1 g) in 20 mL of dry
dichloromethane, 0.5 mL (0.75 mmol) of chlorosulfuric acid was added drop by drop
at room temperature. After 20 min the suspension was filtered and washed with 20
mL of dichloromethane and dried at room temperature to afford HAP@AEPH2ꢀSO3H
as a white powder.
Typical procedure for preparation of 4,4'-(phenylmethylene)bis(3-methyl-1
phenyl-1H-pyrazol-5-ol)
Phenylhydrazine (2 mmol, 0.216 g) was added to a mixture of HAP@AEPH2ꢀSO3H
º
(1.5 mol %, 0.015 g) and ethyl acetoacetate (2 mmol, 0.260 g) at 80 C. The resultant
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mixture was stirred for 1 min. Then, benzaldehyde (1 mmol, 0.106 g) was added to
º
the reaction mixture at 80 C. The viscose mixture was stirred vigorously for the
appropriate time (5 min). Progress of the reaction was monitored by thin layer
chromatography (TLC). After completion of the reaction, the reaction mixture was
washed with hot ethanol (2 × 5 mL) .The resultant hot suspension was filtered off.
The filtrate was cooled and the crude product was precipitated. The crude products
were purified by recrystallization from ethanol (0.427 g, 98 %). To recycle the
catalyst, the precipitate ( HAP@AEPH2ꢀSO3H) was boiled in EtOAc (5 mL) for 10
min and then centrifuged at 10,000 rpm for 5 min. To remove all organic compounds,
the catalyst was refluxed in EtOAc (3×10) for 30 min and centrifuged consecutively.
The recycled catalyst was dried at 50 ºC under vacuum for 3 h and used in the next
run of the model reaction.
Spectral data
61
4,4'-(Phenylmethylene)bis(3-methyl-1-phenyl-1
H
-pyrazol-5-ol) (3a).
White
cream solid; Yield 97 %; mp 170ꢀ173 °C; FTꢀIR (KBr): νmax /cmꢀ1 3058, 3031, 2921,
2553 (OH), 1730, 1599 (C=N),1497, 1449 (C=C), 1412, 1368, 1313, 1263, 1127,
1029, 857, 792, 754, 693, 596, 506, 449; 1H NMR (300 MHz, DMSOꢀd6, ppm)
δ 2.33
(s, 6 H, 2 CH3), 4.98 (s, 1 H, C H), 7.18 –7.27 (m, 7 H, Ph), 7.45 (t, J = 7.8 Hz, 4 H,
13
Ph), 7.72 (d, J = 8.1 Hz, 4 H, Ph), 13.96 (br., 1 H, OH); C NMR (75 MHz, DMSOꢀ
d6 ppm)
δ 12.1, 33.5, 120.9, 126.0, 126.3, 127.6, 128.6, 129.0, 129.4, 137.7, 142.6,
146.8; MS, m/z (%): 259 [M+ꢀ177], 183 [M+ꢀ251], 172 [M+ꢀ264].
4,4'-((4-Hydroxyphenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3b).
62
Yellow solid; Yield 95 %; mp 159ꢀ162 °C; FTꢀIR (KBr) νmax /cmꢀ1 3145 (OH),
3068, 2921, 2774, 2663, 2582 (OH), 1600 (C=N), 1580, 1504, 1454 (C=C), 1371,
1275, 1245, 1173, 1111, 1029, 867, 816, 779, 749, 690, 583, 498, 453; 1H NMR (300
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MHz, DMSOꢀd6, ppm) δ 2.31 (s, 6 H, 2 CH3), 4.87 (s, 1 H, CH), 6.68 (d, J = 8.7 Hz, 2
H, Ph), 7.06 (d, J = 8.4 Hz, 2 H, Ph), 7.25 (t, J = 7.2 Hz, 2 H, Ph), 7.45 (t, J = 7.8 Hz,
4 H, Ph), 7.72 (d, J = 7.8 Hz, 4 H, Ph), 9.21 (s, 1 H, OH), 13.95 (br, 1 H, OH); 13C
NMR (75 MHz, DMSOꢀd6 ppm)
δ 19.0, 32.8, 105.7, 115.3, 120.9, 126.0, 128.5,
129.0, 129.3, 132.7, 137.8, 146.6, 155.8, 155.9; Anal. Calcd for C27H24N4O3: C,
71.67; H, 5.35; N, 12.38. Found: C, 70.71; H, 5.8; N, 11.62 %; MS, m/z (%): 275
[M+ꢀ177], 184 [M+ꢀ268], 173 [M+ꢀ279].
4,4'-((3-Hydroxyphenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3c).
33b
White solid; Yield 93 %; mp 165ꢀ167 °C; IR (KBr) νmax /cmꢀ1 3421 (OH), 3072,
2925, 1708, 1597 (C=N), 1498 (C=C), 1455, 1405, 1368, 1284, 1155, 1029, 996, 754,
692, 503, 412;1H NMR (300 MHz, DMSOꢀd6, ppm)
δ 2.32 (s, 6 H, 2 CH3), 4.89 (s, 1
H, CH), 6.58 (d, J = 7.8 Hz, 1 H, Ph), 6.65ꢀ6.70 (m, 2 H, Ph), 7.07 (t, J = 7.8 Hz, 1 H,
Ph), 7.26 (t, J = 7.8 Hz, 2 H, Ph), 7.46 (t, J = 7.8 Hz, 4 H, Ph), 7.73 (d, J = 7.8 Hz, 4
H, Ph), 9.26 (s, 1H, OH), 13.98 (br, 1H, OH); 13C NMR (75 MHz, DMSOꢀd6 ppm)
δ
12.0, 33.4, 113.3, 114.6, 118.3, 118.8, 120.9, 126.0, 129.4, 129.4, 137.5, 138.1, 144.0,
146.8, 157.6.
4,4'-((2-Hydroxyphenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3d).
17
White solid; Yield 90 %; mp 228ꢀ231 °C; IR (KBr) νmax /cmꢀ1 3411 (OH), 3072,
2921, 2802, 2700, 2561 (OH), 1687, 1597 (C=N), 1574, 1499 (C=C), 1454, 1367,
1286, 1217, 1119, 1041, 912, 879, 847, 751, 687, 606, 586, 506, 440; 1H NMR (300
MHz, DMSOꢀd6, ppm)
δ 2.29 (s, 6 H, 2 CH3), 5.18 (s, 1 H, CH), 6.69ꢀ6.77 (m, 2 H,
Ph), 6.96ꢀ7.02 (m, 1 H, Ph), 7.23ꢀ7.27 (m, 2 H, Ph), 7.44 (t, J= 7.5 Hz, 4 H, Ph), 7.55
(d, J= 7.2 Hz, 1 H, Ph), 7.70 (d, J= 8.1 Hz, 4 H, Ph), 12.34 (br, 1 H, OH); MS, m/z
(%): 275 [M+ꢀ177], 256 [M+ꢀ196], 173 [M+ꢀ279].
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4,4'-((4-Methoxyphenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)) (3e).
63
Yellow solid; Yield 90 %; mp 174ꢀ176 °C; FTꢀIR (KBr) νmax /cmꢀ1 3068, 2974,
2921, 2839, 2610, 1801, 1601 (C=N), 1581, 1507, 1459 (C=C), 1406, 1373, 1279,
1
1249, 1180, 1111, 1033, 966, 812, 751, 691, 596, 498, 442; H NMR (300 MHz,
DMSOꢀd6, ppm)
δ 2.32 (s, 6 H, 2 CH3), 3.71 (s, 3 H, OCH3), 4.91 (s, 1 H, CH), 6.84
(d, J = 8.4 Hz, 2 H, Ph), 7.15ꢀ7.27 (m, 4 H, Ph),7.45 (t, J= 7.8 Hz, 4 H, Ph), 7.71 (d,
J= 7.8 Hz, 4 H, Ph), 13.97 (br, 1 H, OH); 13C NMR (75 MHz, DMSOꢀd6, ppm)
δ
12.1, 32.8, 55.4, 113.9, 120.9, 126.0, 128.6, 129.3, 134.4, 146.6, 157.9; MS, m/z (%):
288 [M+ꢀ178], 258 [M+ꢀ208], 183 [M+ꢀ283].
4,4'-((3-Methoxyphenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3f).
15 Pale yellow solid; Yield 93 %; mp 180ꢀ183 ºC; FTꢀIR (KBr) νmax /cmꢀ1 3517, 3064,
2971, 2885, 2711, 2550 (OH), 1603 (C=N), 1581, 1502, 1485 (C=C), 1405, 1364,
1311, 1274, 1188, 1129, 1042, 1004, 877, 790, 752, 693, 636, 599, 496, 453; 1H NMR
(300 MHz, DMSOꢀd6, ppm)
δ 2.32 (s, 6 H, 2 CH3), 3.69 (s, 3 H, OCH3), 4.93 (s, 1 H,
CH), 6.76ꢀ6.87 (m, 3 H, Ph), 7.18ꢀ7.28 (m, 3 H, Ph), 7.45 (t, J= 7.8 Hz, 4 H, Ph), 7.71
(d, J= 7.8 Hz, 4 H, Ph ), 12.27 (br, 1 H, OH), 13.98 (br, 1 H, OH); Anal. Calcd for
C28H26N4O3: C, 72.09; H, 5.62; N, 12.01, Found: C, 71.9; H, 5.35; N, 11.9 %; MS,
m/z (%): 289 [M+ꢀ177], 259 [M+ꢀ207], 184 [M+ꢀ282].
64
4,4'-(
p
-Tolylmethylene)bis(3-methyl-1-phenyl-1
H
-pyrazol-5-ol) (3g).
White
solid; Yield 93 %; mp 198ꢀ200 °C; FTꢀIR (KBr) νmax /cmꢀ1 3043, 2958, 2922, 2859,
2500 (OH), 1809, 1736, 1600 (C=N), 1580, 1501, 1457 (C=C), 1408, 1372, 1291,
1196, 1131, 1070, 1024, 882, 802, 750, 688, 608, 592, 499, 444; 1H NMR (300 MHz,
DMSOꢀd6, ppm)
δ 2.25 (s, 3 H, PhCH3), 2.33 (s, 6 H, 2 CH3), 4.93 (s, 1 H, CH), 7.08
(d, J = 8.1 Hz, 2 H, Ph), 7.16 (d, J = 7.8 Hz, 2 H, Ph), 7.25 (t, J = 7.5 Hz, 2 H, Ph),
7.45 (t, J = 7.5 Hz, 4 H, Ph), 7.72 (d, J = 7.5 Hz, 4 H, Ph), 13.94 (br, 1 H, OH); 13C
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NMR (75 MHz, DMSOꢀd6, ppm) δ 12.1, 21.0, 33.2, 105.2, 120.9, 126.0, 127.5, 129.1,
129.4, 135.3, 137.8, 139.5, 146.7; Anal. Calcd for C28H26N4O2: C, 74.67; H, 5.82; N,
12.44, Found: C, 74.31; H, 5.8; N, 12.24 %. MS, m/z (%): 273 [M+ꢀ177], 259 [M+ꢀ
191], 184 [M+ꢀ266].
23
4,4'-(m
-Tolylmethylene)bis(3-methyl-1-phenyl-1
H
-pyrazol-5-ol) (3h).
Yellow
solid; Yield 85 %; mp 237ꢀ239 °C; FTꢀIR (KBr) νmax /cmꢀ1 3060, 2949, 2921, 2872,
2540 (OH), 1600 (C=N), 1578, 1499 (C=C), 1457, 1410, 1372, 1289, 1180, 1102,
1024, 902, 800, 752, 691, 597, 499, 442; 1H NMR (300 MHz, DMSOꢀd6, ppm)
δ 2.25
(s, 3 H, PhCH3), 2.32 (s, 6 H, 2CH3), 4.93 (s, 1 H, CH), 7.00ꢀ7.25 (m, 6 H, Ph), 7.45
13
(m, 4 H, Ph), 7.72 (d, J = 7.2 Hz, 4 H, Ph), 13.95 (br, 1 H, OH); C NMR (75 MHz,
DMSOꢀd6, ppm)
δ 12.1, 21.7, 33.5, 120.9, 124.7, 126.0, 127.1, 128.2, 128.5, 129.4,
137.5, 142.6, 146.7; MS, m/z (%): 272 [M+ꢀ178], 258 [M+ꢀ192], 183 [M+ꢀ267].
4,4'-((5-Bromo-2-hydroxyphenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol) (3i). 27 White cream solid; Yield 92 %; mp 265ꢀ267 °C; FTꢀIR (KBr) νmax /cmꢀ1
3448 (OH), 3068, 2970, 2925, 2590 (OH), 1687, 1598, 1574, 1500, 1409, 1376, 1282,
1
1213, 1155, 1106, 902, 861, 784, 747, 669, 596, 514, 436; H NMR (400 MHz,
DMSOꢀd6, ppm)
δ 2.26 (s, 6 H, 2 CH3), 5.10 (s, 1 H, CH), 6.72 (d, J= 8.4 Hz, 1 H,
Ph), 7.15 (d, J= 10.8 Hz, 1 H, Ph), 7.16ꢀ7.24 (m, 2 H, Ph), 7.43 (m, 4 H, Ph), 7.62ꢀ
13
7.69 (m, 5 H, Ph); C NMR (75 MHz, DMSOꢀd6, ppm)
δ 12.1, 27.9, 110.3, 117.3,
121.1, 126.1, 129.4, 130.0, 131.6, 146.8, 153.7.
4,4'-((4-Isopropylphenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
(3j).15 White solid; Yield 80 %; mp 211ꢀ213 °C; FTꢀIR (KBr) νmax /cmꢀ1 3068 (OH),
2958, 2921, 2868, 1797, 1732, 1601 (C=N), 1501, 1415 (C=C), 1371, 1286, 1184,
1
1025, 792, 753, 690, 600, 498, 449. H NMR (300 MHz, DMSOꢀd6, ppm)
δ 1.17 (d,
J= 6.6 Hz, 6 H, 2 CH3), 2.32 (s, 6 H, 2 CH3), 2.79–2.88 (m, 1 H, CH), 4.92 (s, 1 H,
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CH), 7.13ꢀ7.28 (m, 6 H, Ph), 7.45 (t, J= 7.5 Hz, 4 H, Ph), 7.71 (d, J= 7.8 Hz, 4 H, Ph),
12.37 (br, 1 H, OH), 13.97 (br, 1 H, OH); Anal. Calcd for C30H30N4O2: C, 75.29; H,
6.32; N, 11.71, Found: C, 75.1; H, 6.3; N, 11.53 %; MS, m/z (%): 301 [M+ꢀ177], 258
[M+ꢀ220], 184 [M+ꢀ294].
4, 4'-((2-Chlorophenyl)methylene)bis(3-methyl-1-phenyl-1H
-pyrazol-5-ol) (3k). 17
White cream solid; Yield 70 %; mp 235ꢀ237 °C; FTꢀIR (KBr) νmax /cmꢀ1 3062, 2990,
2912, 2868, 2790, 2510 (OH), 1614 (C=N), 1540, 1499 (C=C), 1458, 1400, 1369,
1305, 1217, 1131, 1082, 1033, 898, 837, 792, 746, 689, 637, 568, 501; 1H NMR (300
MHz, DMSOꢀd6, ppm)
δ
2.30 (s, 6 H, 2CH3), 5.15 (s, 1 H, CH), 7.24ꢀ7.34 (m, 4 H,
13
Ph), 7.40ꢀ7.47 (m, 5 H, Ph), 7.68ꢀ7.79 (m, 5 H, Ph), 13.97 (br, 1 H, OH); C NMR
(75 MHz, DMSOꢀd6, ppm)
δ 12.3, 32.1, 121.1, 126.1, 127.3, 128.5, 129.4, 129.9,
130.7, 132.3, 137.6, 139.8, 146.5; MS, m/z (%): 472 [M++2], 294 [M+ꢀ176], 259 [M+ꢀ
211], 184 [M+ꢀ286].
16
4,4'-((4-Chlorophenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3l).
White cream solid; Yield 96 %; mp 214ꢀ216 °C; FTꢀIR (KBr) νmax /cmꢀ1 3060, 2974,
2917, 2549 (OH), 1805, 1736, 1600 (C=N), 1578, 1501, 1486 (C=C), 1408, 1372,
1
1295, 1204, 1086, 1014, 834, 810, 747, 688, 592, 599, 439; H NMR (300 MHz,
DMSOꢀd6, ppm)
δ 2.33 (s, 6 H, 2 CH3), 4.98 (s, 1 H, CH), 7.25ꢀ7.72 (m, 10 H, Ph),
7.71 (d, J = 7.8 Hz, 4 H, Ph); 13C NMR (75 MHz, DMSOꢀd6, ppm)
δ
12.0, 32.9,
104.8, 121.0, 126.1, 128.4, 129.4, 129.6, 131.0, 137.0, 137.7, 141.5, 146.7; MS, m/z
(%): 470 [M+], 292 [M+ꢀ178], 259 [M+ꢀ212].
4,4'-((2,4-Dichlorophenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
(3m).18 White solid; Yield 85 %; mp 228ꢀ230 °C; FTꢀIR (KBr) νmax /cmꢀ1 3072, 2913,
2798, 2570 (OH), 1620 (C=N), 1558, 1498 (C=C), 1462, 1405, 1367, 1311, 1217,
1
1143, 1074, 902, 836, 790, 754, 693, 637, 571, 502; H NMR (300 MHz, DMSOꢀd6,
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DOI: 10.1039/C5RA16236J
ppm)
δ 1.84 (s, 6 H, 2 CH3), 5.59 (s, 1 H, CH), 7.17ꢀ7.45 (m, 9 H, Ph), 7.73 (d, J =
7.5 Hz, 4H), 10.83 (br, 1 H, OH), 11.30 (br, 1H, OH); 13C NMR (75 MHz, DMSOꢀd6,
ppm)
δ 11.7, 34.3, 105.4, 118.3, 118.5, 120.1, 124.6, 125.3, 128.6, 129.0, 129.5,
129.9, 136.1, 137.8, 163.5.
4,4'-((4-Bromophenyl)methylene)bis(3-methyl-1-phenyl-1H
-pyrazol-5-ol) (3n).65
Yellow solid; Yield 97 %; mp 180ꢀ182 °C; FTꢀIR (KBr) νmax /cmꢀ1 3063, 2949, 2922,
2843, 2560 (OH), 1729, 1600 (C=N), 1578, 1499 (C=C), 1456, 1406, 1368, 1306,
1184, 1072, 1026, 1009, 910, 816, 753, 690, 593, 499; 1H NMR (400 MHz, DMSOꢀ
d6, ppm)
δ 2.29 (s, 6 H, 2 CH3), 4.93 (s, 1 H, CH), 7.16ꢀ7.23 (m, 4 H, Ph), 7.44ꢀ7.45
(m, 6 H, Ph), 7.66ꢀ7.67 (m, 4 H, Ph).
4,4'-((3-Nitrophenyl)methylene)bis(3-methyl-1-phenyl-1H
-pyrazol-5-ol) (3o).33b
Yellow solid; Yield 80 %; mp 146ꢀ148 °C; FTꢀIR (KBr) νmax /cmꢀ1 3113, 3076, 2925,
2872, 2712, 2510 (OH), 1785, 1748, 1600 (C=N), 1573, 1527, 1501 (C=C), 1418,
1
1349, 1285, 1200, 1106, 1004, 976, 861, 831, 803, 754, 691, 597, 497, 443; H NMR
(300 MHz, DMSOꢀd6, ppm)
δ 2.37(s, 6H, 2 CH3) 5.17 (s, 1 H, CH), 7.26 (t, J= 7.5
Hz, 2 H, Ph ), 7.46 (t, J= 7.5 Hz, 4 H, Ph ), 7.60 (t, J= 8.1, 1 H, Ph), 7.64ꢀ7.76 (m, 5
H, Ph), 8.08ꢀ8.10 (m, 2 H, Ph), 13.86 (br, 1 H, OH); MS, m/z (%): 303 [M+ꢀ178], 257
[M+ꢀ224], 183 [M+ꢀ228].
4, 4'-((2-Nitrophenyl)methylene)bis(3-methyl-1-phenyl-1H
-pyrazol-5-ol) (3p).32
Pale yellow solid; Yield 70 %; mp 220ꢀ222 °C; FTꢀIR (KBr) νmax /cmꢀ1 3072, 2917,
2798, 2580 (OH),1612 (C=N), 1558, 1521, 1498 (C=C), 1458, 1406, 1372, 1315,
1
1164, 1127, 1070, 898, 837, 788, 755, 677, 628, 567, 502; H NMR (300 MHz,
DMSOꢀd6, ppm)
δ 2.26 (s, 6 H, 2 CH3), 5.43 (s, 1 H, CH), 7.25ꢀ7.28 (m, 2 H, Ph),
7.42ꢀ7.47 (m, 5 H, Ph), 7.66ꢀ7.74 (m, 7 H, Ph), 13.50 (br, 1 H, OH); 13C NMR (75
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DOI: 10.1039/C5RA16236J
MHz, DMSOꢀd6, ppm)
134.7, 137.6, 146.2, 150.0; MS, m/z (%): 483 [M++2], 305 [M+ꢀ176], 259 [M+ꢀ222].
-pyrazol-5-ol) (3q).64
δ 11.9, 29.8, 121.0, 124.5, 126.1, 128.2, 129.4, 130.5, 132.3,
4,4'-(Naphthalen-1-ylmethylene)bis(3-methyl-1-phenyl-1
H
Yellow solid; Yield 95 %; mp 208ꢀ210 °C; FTꢀIR (KBr) νmax /cmꢀ1 3056, 2917, 2573
(OH), 1609 (C=N), 1546, 1497 (C=C), 1457, 1402, 1369, 1315, 1217, 1135, 1037,
1
906, 829, 784, 755, 734, 689, 583, 547, 510; H NMR (400 MHz, DMSOꢀd6, ppm)
δ
2.31 (s, 6 H, 2 CH3), 5.56 (s, 1 H, CH), 7.20 (m, 2 H, Ph), 7.39–7.53 (m, 7 H, Ph),
7.78–7.80 (m, 5 H, Ph), 7.86–8.02 (m, 3 H, Ph).
4,4'-(Pyridin-2-ylmethylene)bis(3-methyl-1-phenyl-1H
-pyrazol-5-ol) (3r).33a Pale
yellow solid; Yield 94 %; mp 230ꢀ232 °C; FTꢀIR (KBr) νmax /cmꢀ1 3060, 2923, 2851,
2690 (OH), 1725, 1596 (C=N), 1498 (C=C), 1457, 1414, 1368, 1312, 1180, 1074,
1025, 833, 755, 691, 592, 502; 1H NMR (300 MHz, DMSOꢀd6, ppm)
CH3), 5.10 (s, 1 H, CH), 7.24–7.74 (m, 13 H), 8.49 (d, J = 7.8 Hz, 1H, Py); 13C NMR
δ 2.28 (s, 6 H, 2
(75 MHz, DMSOꢀd6, ppm)
δ 12.3, 36.9, 120.7, 122.1, 122.4, 125.8, 129.3, 137.6,
138.0, 147.1, 148.6, 161.6.
4,4'-(Pyridin-3-ylmethylene)bis(3-methyl-1-phenyl-1H
-pyrazol-5-ol) (3s).16 Pale
yellow solid; Yield 93 %; mp 237ꢀ239 °C; FTꢀIR (KBr) νmax /cmꢀ1 3060, 2982, 2917,
2581 (OH), 1602 (C=N), 1578, 1498 (C=C), 1456, 1420, 1355, 1290, 1180, 1102,
1028, 863, 800, 753, 692, 637, 592, 506; 1H NMR (300 MHz, DMSOꢀd6, ppm)
δ 2.34
(s, 6 H, 2 CH3), 5.04 (s, 1 H, CH), 7.24 (t, J = 7.5 Hz, 2 H), 7.35 (dd, J = 7.8 Hz, J =
4.8 Hz, 1H), 7.44 (t, J = 7.5 Hz, 4 H), 7.70ꢀ7.75 (m, 5 H), 8.41 (d, J = 4.5 Hz, 1H,
Py), 8.50 (d, J = 2.1 Hz, 1 H, Py); 13C NMR (75 MHz, DMSOꢀd6, ppm)
δ 12.1, 31.5,
104.2, 120.9, 123.7, 125.9, 129.0, 129.3, 135.5, 137.9, 138.5, 146.6, 147.3, 149.0,
157.5; MS, m/z (%): 260 [M+ꢀ177], 232 [M+ꢀ205], 184 [M+ꢀ253].
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